PROJECT SUMMARY: Zika virus (ZIKV) is a flavivirus that has recently caused a large-scale outbreak associated with complications during pregnancy and damage to the developing fetus, including microcephaly. A phenomenon characteristic of some flavivirus infections is antibody-dependent enhancement (ADE), which occurs when antibodies raised against one flavivirus infection cross-react to enhance a closely related flavivirus infection. Because ZIKV is spreading rapidly into regions around the world where other flaviviruses, such as dengue virus (DENV), are currently endemic, it is critical to understand and characterize the extent to which prior infection with closely related flaviviruses exacerbates ZIKV disease. We hypothesize that pre-existing immunity against DENV is a risk factor for ZIKV-mediated complications during pregnancy. In this application, we will determine how pre- existing immunity to DENV affects ZIKV pathogenesis in pregnancy in vivo using a mouse model of infection we recently characterized as well as ex vivo in human placental tissue.